The overarching goal of this application for a K24 Midcareer Investigator in Patient-Oriented Research is to foster training of promising junior investigators in high quality patient-oriented research in male reproduction. The proposed principal investigator, Dr. Amory, has established himself as a gifted researcher and is a dedicated mentor to junior faculty and trainees. With this award, Dr. Amory hopes to continue as a leader in patient-oriented research in the area of male reproduction and to enhance the educational training of clinical trainees through hands-on mentorship, facilitating their individua growth as well as the future of translational research in male reproduction. Infertility affects 10 15% of all couples, and infertility attributable to the male partner accounts for 30-40% of all cases of infertility. The most common form of male infertility involves some type of impairment in spermatogenesis. Unfortunately, most men with infertility do not have a medically treatable cause. Surgical sperm extraction coupled with either in vitro fertilization or intra-cytoplasmic sperm injection offers hope of fertility; however, these procedures are invasive, expensive, unsuccessful in many cases, and don't address the underlying cause of infertility. Therefore, new approaches to the treatment of male infertility are needed. The objective of the work proposed in this application is to obtain knowledge useful to understand the role of retinoic acid in spermatogenesis and male infertility. It is well established in animal models that testicular biosynthesis of retinoic acid is required for spermatogonial differentiation, spermiogenesis and spermiation. However, in contrast to the situation in experimental animals, there has been almost no work examining the role of retinoic acid in human spermatogenesis. Recently, our group found that intratesticular retinoic acid is significantly reduced in men who have sub-normal sperm parameters, suggesting that intratesticular retinoic acid deficiency may be related to impaired spermatogenesis in man. With this grant, we propose to examine the role of intratesticular retinoic acid in men presenting with male infertility. In the first aim of this proosal, we will investigate the relationship between intratesticular retinoic acid and spermatogenesis using an observational study in testicular tissue from men undergoing sperm retrieval procedures for infertility treatment. In the second aim, we will conduct a pilot clinical trial of retinoic acid administration to men with infertility from poor sperm quality to determine whether retinoic acid improves ejaculated sperm parameters. Taken together, these experiments will greatly improve our understanding of the relationship between intratesticular retinoic acid and spermatogenesis in man, and have the potential to initiate a novel medical approach to the treatment of male infertility.